Comprehensive treatment of patients with stage I NSCLC

(1) Preferred surgical treatment includes lobectomy with systematic hilar and mediastinal lymph node dissection and partial lobectomy with selective lymph node dissection, which can be minimally invasive or open-heart surgery such as TV thoracoscopy or robotic surgery.
(2) Anatomic lung segmental or wedge resection with systematic hilar and mediastinal lymph node dissection or sampling can be considered for some stage IA NSCLC patients with advanced age or low lung function.
(3) Postoperative adjuvant chemotherapy, radiation therapy and targeted drug therapy are not recommended for patients with completely resected stage IA and IB NSCLC.
(4) Re-operation is recommended for stage I lung cancer with positive margins, and postoperative combination radiotherapy is recommended for patients who cannot be operated again for any reason.
(5) For patients with severe medical comorbidities, advanced age, or refusal of surgery, stereotactic radiation therapy can be used.

Comprehensive treatment for patients with stage II NSCLC

(1) Preferred surgical treatment is lobectomy plus systemic hilar and mediastinal lymph node removal or sampling.
(2) Anatomic lung segmental or wedge resection plus systematic hilar and mediastinal lymph node dissection or sampling may be considered in patients with advanced age or low lung function.
(3) Postoperative adjuvant chemotherapy with two platinum-containing agents is recommended for patients with complete resected stage II NSCLC.
(4) Whole chest wall resection should be performed when the tumor invades the mural pleura or chest wall. The extent of resection should be at least 2 cm from the upper and lower margins of the nearest rib, and the length of resection of the invaded rib should be at least 5 cm from the tumor.
(5) Reoperation is recommended for stage II lung cancer with positive margins, and for patients who cannot be reoperated for any reason, postoperative concurrent radiotherapy is recommended if the patient is physically able, and radiotherapy should be started as soon as possible.

Comprehensive treatment of patients with stage III NSCLC

Locally advanced NSCLC is defined as patients with TNM stage III. Multidisciplinary combination therapy is the best option for stage III NSCLC. Locally advanced NSCLC is divided into 2 major categories: resectable and unresectable.
(1) Resectable locally advanced NSCLC includes
(1) For patients with T3-4N1 or T4N0, surgery + adjuvant chemotherapy or radical radiotherapy or chemotherapy is recommended, and neoadjuvant therapy can be considered.
②For cases with single mediastinal lymph node enlargement of <3cm in diameter in stage N2, or two groups of mediastinal lymph node enlargement without fusion, and complete resection is expected, multidisciplinary discussion is recommended, and neoadjuvant chemotherapy±radiotherapy+surgery, or surgery+chemotherapy±radiotherapy is recommended. For EGFR mutation-positive patients, surgery + adjuvant EGFR-TKI therapy ± postoperative radiotherapy is used. Pre-operative mediastinoscopy, ultrasound-guided transbronchial needle aspiration biopsy or ultrasound endoscopy-guided fine-needle aspiration biopsy is recommended to clarify the N2 staging, followed by pre-operative neoadjuvant chemotherapy or neoadjuvant radiotherapy or chemotherapy, and then surgical treatment. For patients with multiple N2 lymph node metastases with the expectation of complete resection, radical simultaneous radiotherapy is recommended first because the risk of recurrence is significantly higher than that of single-site N2; a combination of neoadjuvant chemotherapy +/- radiotherapy + surgery ± adjuvant chemotherapy ± postoperative radiotherapy can also be considered. For patients with positive EGFR mutations, surgery + combined adjuvant EGFR-TKI therapy ± post-operative radiotherapy is also recommended.
(3) For stage II-IIIA NSCLC, based on the data on the benefit of targeted adjuvant therapy in the ADAURA, EVIDENCE, ADJUVANT and EVAN studies, EGFR mutation testing is therefore recommended for patients with stage II-IIIA non-squamous cell NSCLC, N1 to 2.
(2) Unresectable locally advanced NSCLC includes
(1) Some stage IIIA (N2) patients with imaging suggestive of mediastinal fusion-like enlarged lymph nodes and positive mediastinoscopy, ultrasound-guided transbronchial needle aspiration biopsy or ultrasound endoscopy-guided fine-needle aspiration biopsy for NSCLC, which should be clearly identified as unresectable patients after MDT discussion of chest tumor.
②Patients with IIIB/IIIC.
③If unresectable locally advanced NSCLC, such as PS0-1 score, then the recommended first choice of treatment is synchronous chemoradiotherapy, and if there is no disease progression after synchronous radiotherapy, the addition of dovalizumab maintenance therapy can be considered.

Comprehensive treatment for patients with stage IV NSCLC

Patients with stage IV NSCLC should obtain tumor tissue for gene mutation testing, such as EGFR, ALK, and ROS1, before starting treatment, and decide the appropriate treatment strategy based on the above genetic status. The aim of treatment is to improve the quality of life and prolong the survival of patients.
(1) Treatment of stage IV NSCLC patients with isolated brain, adrenal and lung metastases
For patients with isolated brain metastases and resectable lung lesions, the brain lesions can be surgically removed or treated with stereotactic radiation therapy, while the primary lesions in the chest are treated according to the principle of staging.
Patients with isolated adrenal metastases and resectable pulmonary lesions should consider surgical resection of the adrenal lesions and staged treatment of the primary lesions in the chest.
(3) Isolated nodules in the contralateral lung or other lobes of the ipsilateral lung may be treated according to the respective staging of the two primary tumors if the primary lung lesion is surgically resectable; if surgery is performed, adjuvant therapy will be guided by pathology.
(2) Systemic therapy for patients with stage IV NSCLC
(1) First-line treatment with EGFR-TKI is recommended for stage IV NSCLC patients with EGFR gene-sensitive mutations; first-line treatment with ALK inhibitors such as crizotinib, aletinib or ceritinib is recommended for ALK fusion gene positive patients; first-line treatment with crizotinib is recommended for ROS1 fusion gene positive patients.
Patients with stage IV NSCLC who are negative for EGFR genes, ALK and ROS1 fusion genes or whose mutation status is unknown should start platinum-containing two-drug chemotherapy as early as possible if the ECOG PS score is 0-1, and systemic therapy with immune checkpoint inhibitors (e.g., PD-1 monoclonal antibody) or bevacizumab (non-squamous carcinoma) can be added to this therapy; if the patient is PD-L1 positive (TPS ≥ 1), pablizumab can be administered. Pabrolizumab monotherapy is available, with more significant immunotherapy benefit in patients with high PD-L1 expression (TPS ≥ 50); patients with high PD-L1 expression (TC ≥ 50 or IC ≥ 10) may also receive atelelizumab monotherapy. For patients who are not suitable for platinum-based therapy, a non-platinum-based two-drug combination regimen chemotherapy may be considered.
(iii) Patients with advanced NSCLC with an ECOG PS score of 2 should be given single-agent chemotherapy, but cytotoxic chemotherapy should be used with caution in patients with an ECOG PS score >2.
④ For elderly patients, evidence does not support the use of age as the sole basis for choosing chemotherapy regimens, but must be evaluated in conjunction with organ function indicators and ECOG PS status. Patients with ECOG PS score 0 to 1 may still be considered for platinum-containing two-drug regimens and patients with ECOG PS score 2 for single-agent chemotherapy; systemic chemotherapy is not recommended for those with severe organ dysfunction and those with ECOG PS score 2 or higher.
⑤ Second-line treatment options include docetaxel, pemetrexed, PD-1 monoclonal antibody, or targeted therapy. For patients with positive driver mutations, second-line therapy should be prioritized with molecularly targeted agents if the corresponding molecularly targeted agents were not used in first-line and maintenance therapy; for patients who are resistant to first-line EGFR-TKIs and positive for EGFR T790M mutations, second-line therapy should be prioritized with third-generation EGFR-TKI such as oseltinib, ametinib or vomitinib. For ALK fusion-positive patients who develop resistance after first-line crizotinib treatment, second-line treatment may include ceritinib or aletinib. In case of oligogenic or CNS progression after resistance to first-line molecular targeted therapy, the combination of targeted therapy with local therapy, such as radiotherapy or surgery, may be continued. For patients with resistance to first-line EGFR-TKI or ALK inhibitors, second-line therapy may also include a two-drug platinum-containing regimen or a single-agent chemotherapy regimen based on the patient’s ECOG PS score, or in the case of non-squamous cancer, a combination of anti-vascular agents such as bevacizumab. For patients with negative driver genes, if PD-1 monoclonal antibody is not applied in the first line, nabumetinumab treatment can be considered in the second line.
(6) Patients with stage IV NSCLC with an ECOG PS score >2 generally do not benefit from chemotherapy and are recommended for best supportive care. Based on systemic treatment, appropriate local treatment can be chosen for specific local conditions in order to improve symptoms and quality of life.
(7) High-throughput sequencing (HTS) has been widely used in clinical practice for the detection of genetic mutations, assessment of tumor mutational load, and to determine the resistance mechanism of molecularly targeted drugs and to guide the next step of treatment.